Glioblastoma multiforme (GBM) is the most malignant and invasive human brain tumor and has a 5-year survival rate that remains at less than 5%, despite the use of intensive treatment modalities. The prognosis has remained dismal in spite of aggressive multimodal therapy through implementation of a newer generation of targeted molecular therapies alone or in combination (Munson J, Bonner M, Fried L, Hofmekler J, Arbiser J et al. (2013) Identifying new small molecule anti-invasive compounds for glioma treatment. Cell Cycle 12:2200-9). The development of new treatments is critical in order to improve the outcomes of patients with GBM. In contrast to chemotherapeutically targeting a single protein or signaling pathway in cancer cells, the concept of targeting a master regulator in cancer cells, such as heat shock protein 90 (Hsp90) has gained appeal and may hold promise for highly heterogeneous and invasive cancers like GBM that are refractory to current treatments (Munson J, Bonner M, Fried L, Hofmekler J, Arbiser J et al. (2013) Identifying new small molecule anti-invasive compounds for glioma treatment. Cell Cycle 12:2200-9; and Xu W, Neckers L (2007) Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells. Clin Cancer Res. 13:1625-9). Newer generations of small molecule Hsp90 inhibitors (Hsp90i) that target the ATP binding pocket are showing promising efficacy against a broad range of cancers, along with improved safety profiles. However, the outcomes of Hsp90i clinical trials, while promising, have been mixed at best, indicating the need for more efficacious Hsp90i (McDonald E, Workman P, Jones K. (2006) Inhibitors of the HSP90 molecular chaperone: attacking the master regulator in cancer. Curr Top Med Chem. 6:1091-107; Sidera K, Patsavoudi E (2014) HSP90 inhibitors: current development and potential in cancer therapy. Recent Pat Anticancer Drug Discov 9:1-20; and Travers J, Sharp S, Workman P (2012) HSP90 inhibition: two-pronged exploitation of cancer dependencies. Drug Discov Today (5-6):242-52). There are at least 13 Hsp90 inhibitor drug candidates that are currently undergoing clinical trials for multiple indications as single agents or combination therapy (Sidera K, Patsavoudi E (2014) HSP90 inhibitors: current development and potential in cancer therapy. Recent Pat Anticancer Drug Discov 9:1-20). These drugs represent a diverse array of chemical matter stemming from natural product scaffolds to synthetic structure-based design (Sidera K, Patsavoudi E (2014) HSP90 inhibitors: current development and potential in cancer therapy. Recent Pat Anticancer Drug Discov 9:1-20; and Porter J R, Fritz C C, Depew K M (2010) Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. Curr Opin Chem Biol 14:412-20). Significantly, of the vast number of small molecule Hsp90 inhibitors described, only a small number are known to cross the blood brain barrier, which is an absolute drug requirement for cancers of the CNS, such as GBM (Bao R1, Lai C J, Qu H, Wang D, Yin L, et al (2009) CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res. 15:4046-57; Ernst J T, Neubert T, Liu M, Sperry S, Zuccola H, et al (2014) Identification of novel HSP90α/β isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease. J Med Chem 57:3382-400; Sauvageot C M, Weatherbee J L, Kesari S, Winters S E, Barnes J, et al. (2009). Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro Oncol. 11:109-121; and Zhu H, Woolfenden S, Bronson R T, Jaffer Z M, Barluenga S, et al. (2010) The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme. Mol Cancer Ther. 9:2618-2626).
Hsp90 may be considered a master regulator in cancer cells by virtue of its role as a chaperone protein whose association is required for the stability and function of multiple mutated, chimeric and over-expressed signaling proteins that promote the growth and/or survival of cancer cells. The promise of inhibition of such a master regulator for cancer therapy is the potential to cause combinatorial inhibition of multiple oncogenic signaling pathways simultaneously. With the recent discovery of feedback loops that effectively negate the efficacy of selectively targeted anti-cancer agents, there is renewed interest in such a multi-pronged approach (Altieri D C, Stein G S, Lian J B, Languino L R (2012) TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta. 1823:767-773; and Siegelin M D (2013) Inhibition of the mitochondrial Hsp90 chaperone network: a novel, efficient treatment strategy for cancer? Cancer Lett 333:133-46).
Hsp90 and the two compartmentalized homologues of Hsp90 that are found in cells, i.e., endoplasmic reticular grp94 and mitochondrial TRAP1, show increased levels and/or increased ATPase activity in many cancers including GBM in response to cellular stress (Okayama S, Kopelovich L, Balmus G, Weiss R S, Herbert B S, et al (2014) p53 protein regulates Hsp90 ATPase activity and thereby Wnt signaling by modulating Ahal expression. J Biol Chem 289:6513-25; Burrows F, Zhang H, Kamal A (2004) Hsp90 activation and cell cycle regulation. Cell Cycle 3:1530-6; Ferrarini M, Heltai S, Zocchi M R, Rugarli C. (1992) Unusual expression and localization of heat-shock proteins in human tumor cells. Int J Cancer. 51:613-9; Costantino E, Maddalena F, Calise S, Piscazzi A, Tirino V, et al (2009) TRAP1, a novel mitochondrial chaperone responsible for multidrug resistance and protection from apoptosis in human colorectal carcinoma cells. Cancer let 279:39-46; Kang B H, Plescia J, Dohi T, Rosa J, Doxsey S J, et al (2007) Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131:257-70; McLaughlin M, Vandenbroeck K (2011) The endoplasmic reticulum protein folding factory and its chaperones: new targets for drug discovery? Br J Pharmacol 162:328-45; and Siegelin M D, Plescia J, Raskett C M, Gilbert C A, Ross A H, et al (2010) Global targeting of subcellular hsp90 networks for therapy of glioblastoma. Mol Cancer Ther 9:1638-1646. Given the significant homology within the ATP binding pockets of these Hsp90 homologues, new generations of Hsp90 inhibitors with broadened activity to include one or both of these homologues could improve efficacy for this inhibitor class (Felts S J, Owen B A, Nguyen P, Trepel J, Donner D B, et al (2000) The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J Biol Chem 275:3305-12). Inhibitors that target one or both mitochondrial Hsps (TRAP1 and mitochondrial Hsp90) are particularly attractive based on the finding that mitochondrial Hsps exhibit antiapoptotic and antioxidant proprieties in cancer cells (Matassa D S1, Amoroso M R, Agliarulo I, Maddalena F, Sisinni L, et al (2013) Translational control in the stress adaptive response of cancer cells: a novel role for the heat shock protein TRAP1. Cell Death Dis 4:e851:1-10). TRAP1 promotes tumor growth by virtue of its role in a number of protective processes that include protection against mitochondrial apoptosis and drug resistance (Chae Y C, Caino M C, Lisanti S, Ghosh J C, Dohi T, et al (2012) Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s. Cancer Cell 22:331-344; Maddalena Fl, Sisinni L, Lettini G, Condelli V, Matassa D S, et al (2013) Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. Mol Oncol 7:895-906; and Wang R, Shao F, Liu Z, Zhang J, Wang S, et al (2013) The Hsp90 inhibitor SNX-2112, induces apoptosis in multidrug resistant K562/ADR cells through suppression of Akt/NF-jB and disruption of mitochondria-dependent pathways. Chemico-Biological Interactions 205:1-10). Inhibitors against cytosolic Hsp90 and mitochondrial Hsps have been shown to be effective against GBM, both in vitro and in vivo (Gaspar N, Sharp S Y, Eccles S A, Gowan S, Popov S, et al. (2010) Mechanistic evaluation of the novel HSP90 inhibitor NVP-AUY922 in adult and pediatric glioblastoma. Mol Cancer Ther. 9:1219-1233). In view of these findings, dual Hsp90/TRAP1 inhibitors will be of significant therapeutic benefit, particular in the treatment of GBM and other cancers.